P-048: INFLUENCE OF SEVEN GENETIC POLYMORPHISMS ON THE RESPONSE TO SICKLE CELL DISEASE THERAPY WITH HYDROXYUREA
Authors: FRANCO SANTOS O., DE ASSIS BOY K., TOGNON R., MENEGHIN MENDONÇA L., PINHO SANTOS A., DE OLIVEIRA WERNECK RODRIGUES D., VELLOSO RODRIGUES C., SOUZA ALMEIDA SILVA GERHEIM P.
Journal: HemaSphere (2022)

Purpose: Sickle cell disease (SCD) is a serious public health problem worldwide. Currently, hydroxyurea (HU) is the most widely used drug in SCD as it promotes a reduction in severity of sickle cell events, improves hematological parameters and increases the quality and expectancy of life. Despite the evident benefits of HU, there is significant inter-individual variability in pharmacological response and genetic factors seem to be associated. The aim of this study was evaluate the individual variability of pharmacological response to treatment with HU, analyzing pharmacogenetic markers and hematological parameters of patients with not treated SCD and after treatment. Materials and methods: 185 patients with SCD treatment (n=93) and without treatment (n=92) with HU followed at Fundação Hemominas of Governador Valadares/Minas Gerais (MG)- Brazil were evaluated. The mean levels of hemoglobin (Hb), hematocrit, reticulocytes, global leukometry and fetal hemoglobin (HbF) were assessed before and after treatment. Patients were genotyped by real-time PCR (qPCR) for the polymorphisms G>T (rs1799983) and T>C (rs2070744) on the endothelial nitric oxide synthase (eNOS) gene, C>T (rs17599586) of arginase type 1 (ARG1) gene, A>C (rs766432) and G>A (rs4671393) of the B-cell lymphoma/leukemia 11A (BCL11A) gene, G>A (rs9960464) of the Urea Transporter (UTA) gene and A>G (rs2182008) of the Fms-related tyrosine kinase 1 (FLT1). The Ethics Committee has approved this study. Results: The average age of patients was 15.8±11.3 years, among which 54% were men. Genotypic and allele frequencies for polymorphisms in the gene of eNOS (rs1799983: G=0.76; T=0.26/rs2070744: T=0.65;C=0.35), ARG1 (C=0.86; T=0.14), BCL11A (rs4671393: G=0.76; A=0.24/ rs766432: A=0.76;C=0.24), UTA (G=0.61; A=0.39), and FLT1 (rs2182008: G=0.92; A=0.08) were in Hardy-Weinberg equilibrium and were similar to those found in other populations. In the group of patients treated with HU, those with the GT genotype for the polymorphism in eNOS gene had higher baseline Hb values when compared to GG patients (p=0.033). When patients were grouped according to HU response profile in “responders” (HbF ≥ 20%) or “non-responders” (HbF < 20%), it was found that those with the AC and CC genotypes in the BCL11A and GA gene in the UTA gene responded more effectively to drug treatment than patients homozygous for the most frequent allele. No significant influences were found related to other polymorphisms or the response to HU after analyses by logistic regression. Conclusion: This study is pioneer in describing the frequencies of 7 polymorphisms in 5 candidate genes in a population of individuals with SCD treated with HU in the state of MG. The findings suggest that patients with the GT genotype in the eNOS gene (rs1799983) have higher Hb values and that the polymorphisms in the BCL11A (rs766432) and UTA seem to affect the hematological response to HU. Support: FAPEMIG (APQ-02608-14, PPSUS/APQ-03560-13) and UFJF. The authors do not declare any conflict of interest